The objective of this project is to determine the pre- or postsynaptic localization and the molecular mechanism of the cholinergic defects which appear in Huntington's chorea and tardive dyskinesia and to find more specific pre- and postsynaptic muscarinic agents for therapy than those (e.g. physostigmine, scopolamine, atropine and oxotremorine) presently used. Studies on binding of antipsychotic drugs of the phenothiazine and butyrophenon class and of tricyclic antidepressants to the postsynaptic muscarinic receptor which is coupled to generation of cGMP and to the presynaptic muscarinic autoreceptor which regulates acetylcholine release from cerebral cortical, striatal and hippocampal cholinergic nerve endings are suggested. The binding studies will be carried out measuring both agonist binding and generation of cGMP in response to receptor occupancy. Measurements of interference by psychoactive drugs with both of these processes will be carried out in order to calculate the functional blockade of muscarinic action. Further studies on the muscarinic receptor mediated increase in cGMP levels in different regions of the brain and in N1E 115 neuroblastoma cells are suggested in order to find the site of action of blockade by psychoactive drugs and to find methods to circumvent the cholinergic receptor when it is lost or blocked by antipsychotic or antidepressant drugs and to be able to stimulate cGMP synthesis directly. Studies on acetylcholine release from "a purely presynaptic preparation" of synaptosomes are suggested for the characterization of the role of dopamine receptor, muscarinic autoreceptor and opiate receptor in regulation of acetylcholine output in the hippocampus, striatum and cerebral cortex. The possible role of cGMP in presynaptic muscarinic autoreceptor action will be investigated.